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NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal GI adverse events. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge.
NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue.
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Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies. More than 5, years have passed since a Greek physician prescribed extracts of willow bark for musculoskeletal pain. Nowadays, NSAIDs are among the most commonly used drugs worldwide and their analgesic, anti-inflammatory and anti-pyretic therapeutic properties are thoroughly accepted.
Like many other drugs, however, NSAIDs are associated with a broad spectrum of side effects, including gastrointestinal GI and cardiovascular CV events, renal toxicity, increased blood pressure, and deterioration of congestive heart failure among others. In this review, we will focus on upper and lower GI tract injury. These upper GI side effects include troublesome symptoms with or without mucosal injury, asymptomatic mucosal lesions, and serious complications, even death.
Generally, these lesions have no clinical significance and tend to reduce or even disappear with chronic use, probably because the mucosa is adapted to aggression [ 3 , 4 ]. A meta-analysis of the available trials from the Cochrane collaboration concluded that COX-2 selective inhibitor celecoxib was associated with less symptomatic ulcers, endoscopically detected ulcers and discontinuations for GI adverse events compared with ns-NSAIDs naproxen, diclofenac, ibuprofen and loxoprofen [ 5 ].
Unfortunately, these symptoms are not predictive of the presence of mucosal injury. Case-control studies and a meta-analysis have shown that the average relative risk RR of developing uncomplicated or complicated peptic ulcer is fourfold and fivefold in NSAIDs users compared with nonusers [ 7 — 9 ].
The risk is suggested to be higher during the first month of treatment RR, 5. That is the main reason to say that prevention therapies should be implemented based on the presence of risk factors and not after the occurrence of dyspeptic symptoms.
Risk factors for nonsteroidal anti-inflammatory drug-related gastrointestinal complications. Concomitant therapy with antiplatelet agents, anticoagulants, corticosteroids. RR of GI complications 2 to 4: rofecoxib, meloxicam, nimesulide, sulindac,. RR of GI complications 4 to 5: tenoxicam, naproxen, difflunisal and. GI damage is dose dependent, and slow-release formulations and drugs with longer half-life also have greater toxicity.
These differences may be attributed in part to the dose and formulations. This isoenzyme expression can be induced by inflammatory mediators in multiples tissues and can have an important role in the mediation of pain, inflammation and fever. Selective COX-2 inhibitors inhibit this enzyme, but keep prostaglandin production via COX-1, which is involved in the maintenance of GI mucosal integrity.
A systematic review of randomized controlled trials RCTs showed that selective COX-2 inhibitors celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib produced significantly fewer ulcers RR, 0.
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One should point out that these studies were nonrandomized trials and the data result from indirect comparisons. The review involved 7, patients and concluded that COX-2 inhibitors reduce significantly the risk of perforation, obstruction, and bleeding RR, 0.
Nitric oxide and hydrogen sulfide are potent vasodilator molecules and increase mucosal protection, keeping its wholeness. This has led to the concept that coupling a NSAID and nitric oxide or hydrogen sulfide molecules could overcome the negative effects produced by prosta-glandin inhibition.
Naproxcinod was the first and only COX-inhibiting nitric oxide donator investigated in clinical trials, showing a slight improvement in GI tolerability compared with naproxen. Owing to the lack of outcome studies and potential side effects not yet fully evaluated, this compound has not obtained the green light to be commercialized by official drug agencies in Europe and the USA [ 22 ].
NSAIDs that release hydrogen sulfide are being investigated in preclinical models. Over the past decades, there have been significant changes in the rate of hospitalizations due to GI complications.
A multicenter study reported that rates of hospitalization for NSAID gastropathy first increased from 0. Looking at reported time trends for hospitalizations due to GI events overall and not only NSAID-associated GI complications , we could say that hospitalizations owing to uncomplicated peptic ulcer are decreasing over time [ 24 , 25 ]. However, there were discrepancies concerning hospitalizations owing to complicated ulcers.
Generally, studies that reported decreasing peptic ulcer bleeding rates were more recent and were population based. In this regard, it is interesting to highlight a Spanish study by Lanas and colleagues published in [ 26 ]. The authors showed that the incidence per , person-years of hospitalizations due to upper GI ulcer bleeding and perforations decreased over time from This tendency contrasted with a progressive and significant increase in the incidence of hospitalizations due to lower GI complications colonic diverticular and angiodysplasia bleeding, and a small increasing trend of intestinal perforations.
Table constructed using data from [ 28 ]. NSAID, nonsteroidal anti-inflammatory drug. Time trends of gastrointestinal events. Estimated number of events per , person-years on the basis of the adjudication of events in the validation process. Figure constructed using data from [ 27 ]. GI, gastrointestinal. CE studies in healthy subjects taking either short-term or long-term NSAIDs have presented evidence of mucosal damage in the small bowel.
A systematic review reported an increase of fecal blood loss 0. The clinical significance of these findings is not yet clear. The prevalence of NSAID-related lower GI adverse effects, including both clinical and subclinical manifestations, may exceed those detected in the upper GI tract and include a wide spectrum of lesions.
Furthermore, in many instances, there is no close relationship between demonstrable lesions on the upper GI tract and GI blood loss [ 39 ]. The development of increased gut permeability and mucosal inflammation are the most frequent abnormalities in NSAID users [ 41 ]. Short-term studies with COX-2 selective inhibitors have shown that these agents do not increase intestinal permeability [ 45 , 46 ]. Small intestine permeability is necessary for the subsequent development of small intestine inflammation, which is associated with blood and protein loss, but it is often silent [ 48 ].
CE and enteroscopic studies have shown that NSAID use induces erythema, mucosal hemorrhage, erosions and intestinal ulceration in the small bowel, confirming previous autopsy data [ 49 , 50 ]. However, in the MEDAL trial, although the incidence of lower GI events exceeded that seen in the upper GI tract patients were advised to take PPIs if they had risk factors , there were no benefits of etoricoxib over diclofenac when looking at the incidence of lower GI complications [ 30 ].
A systematic review found a positive association of complicated diverticular disease with ns-NSAID use [ 57 ]. The specific risk for diverticular bleeding was increased 3. Patients developing an upper and lower GI complication are at risk of dying [ 59 ]. A recent study published by Sonnenberg looking at the time trends of ulcer disease in a representative sample of six European countries concluded that the risk of death from gastric and duodenal ulcers increased among consecutive generations born during the second half of the nineteenth century until shortly before the turn of the century and then decreased in all subsequent generations [ 62 ].
The increase in NSAID consumption or introduction of potent anti-secretory medications has not affected the long-term downward trends of ulcer mortality. A recent Spanish population-based study looking at patients hospitalized because of GI adverse events between and reported that, overall, there was a statistically significant decrease in the sex-standardized and age-standardized mortality rate owing to a decrease in the number of patients hospitalized because of GI events over time [ 27 ].
When stratified by source, the decrease was not present in patients with lower GI events. However, the case fatality rate did not change over the study period for all types of GI complication events. One should note that the mean age of fatal cases remained constant during the study period. The authors concluded that the reduction observed in mortality associated with hospitalizations because of GI events was due to the observed decreased rate of upper GI events, probably associated with our ability to prevent those complications [ 15 , 63 ].
One should also highlight that recent publications note that most peptic ulcer bleeding-related deaths are not a direct consequence of the bleeding ulcer itself. Instead, mortality derives from cardio-pulmonary conditions, multiorgan failure or terminal malignancy, suggesting that improving treatments of the bleeding ulcer may affect mortality very little [ 64 ].
Recognition of these associations is essential for the improvement of therapeutic strategies that focus not only on the GI tract, but also on providing supportive care and preventing complications and key-organ failure.
The identification of non-GI risk factors associated with poor outcomes in peptic ulcer bleeding patients and a multidisciplinary approach for high-risk patients should help to reduce this outcome. The presence of upper GI symptoms dyspepsia and reflux is not predictive of the occurrence of GI complications.
The most relevant upper GI risk factors are history of prior peptic ulcer, older age and concomitant use of low-dose aspirin. Over the past decade, hospitalizations due to upper GI complications have decreased, whereas the number of lower GI complications has increased. Most peptic ulcer bleeding-associated deaths are not direct sequelae of the bleeding ulcer itself. Instead, mortality derives from cardiopulmonary conditions, multiorgan failure and malignant condition.
Multinational Etoricoxib and Diclofenac Arthritis Long-term.
Vioxx Gastrointestinal Outcomes Research. The supplement was proposed by the journal and developed by the journal in collaboration with the Guest Editor. The Guest Editor assisted the journal in preparing the outline of the project but did not have oversight of the peer review process. Publication of this supplement has been supported by Horizon Pharma Inc. Duexis ibuprofen and famotidine is a product marketed by the sponsor. Table of Contents Abstract Introduction Nonsteroidal anti-inflammatory drug-associated upper gastrointestinal damage Nonsteroidal anti-inflammatory drug-associated lower gastrointestinal damage Nonsteroidal anti-inflammatory drug-related mortality Key messages Declarations References.
Review Open Access. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage.
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Abstract NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. A meta-analysis of 16 studies showed that the odds ratio for peptic ulcer in patients with both risk factors H. Some of these risk factors can be modified. For example, two studies have showed that H.
Table 1 Risk factors for nonsteroidal anti-inflammatory drug-related gastrointestinal complications. As we have pointed out above, the association of NSAID use with upper GI damage is well documented; however, the association with damage to the lower GI tract has not been widely studied and remains poorly characterized. Recent publications have shown that the incidence of lower GI complications including ulceration, bleeding, obstruction or perforation , many of them related to NSAID and ASA use, is increasing whereas the incidence of upper GI complications is decreasing [ 28 ] Figure 1.
Figure 1 Time trends of gastrointestinal events. Arthritis Rheum.
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Am J Ther. Am J Gastroenterol. PubMed Google Scholar Lanas A, Hunt R: Prevention of anti-inflammatory drug induced gastrointestinal damage: beneficts and risks of therapeutic strategies.
Ann Med. Arthritis Res Ther. An overview of epidemiologic studies published in the s.